We propose a collaboration between Columbia University, in New York, and the Macedonian Academy of Sciences and Arts, in Skopje, to investigate abnormalities of cerebral white matter, and particularly myelin, in schizophrenia. The preludes to this project are a successful collaboration to collect autopsy brains in Macedonia for research on schizophrenia, a successful collaboration to establish electron microscopy in Macedonia for the study of schizophrenia, and a longstanding conviction, continually receiving reinforcement, that subtle abnormalities of myelin are important in schizophrenia. The project consists of 4 elements, each designed to advance our knowledge of schizophrenia, the training of Macedonian scientists, and an important, sustainable scientific capability in Macedonia. First, we propose to use electron microscopy to measure the sizes of axons and their myelin sheaths in the white matter, in order to determine whether these are abnormal in schizophrenia, and whether age-related changes are different in people with and without schizophrenia. This will involve aspiring Macedonian scientists in schizophrenia research and will solidify the role of our electron microscopy facility as a national resource. Second, we propose to use stereology to determine densities of oligodendrocytes and microglia in white matter. This will be a novel use of stereology, which generally shuns the measurement of densities because of unknown changes in tissue volumes, but these difficulties can be overcome. It is not clearly known what changes in the cellular composition of white matter take place in schizophrenia or in normal aging. We are already training a Macedonian forensic pathologist in stereology, and the project will support a facility in which he can train others. Third, we and others have strong evidence for abnormal levels of certain myelin-related proteins or their mRNA in schizophrenia, but in general, only the most abundant proteins have been investigated. Proteomic techniques exist that can measure essentially all proteins in a piece of tissue simultaneously. We will bring a Macedonian scientist to begin to analyze samples while learning to use state-of-the-art label-free proteomics in the core facility at Columbia, after which the Ministry of Science in Macedonia will support the purchase of similar instrumentation to establish a world-class facility in the Macedonia, where analysis will continue, with continued collaborative support from the director of the facility at Columbia. Fourth, we will bring a Macedonian expert in informatics to the Columbia genome facility, where he will learn to process raw data from high-throughput RNA sequencing (RNA-seq) that will elucidate levels of essentially all mRNA species in our samples, and he will train students in Macedonia in these methods, which have wide biological applicability. The final outcome should be a major role for Macedonia in solving a difficult and important problem, and at least four core facilities for research and training. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating illness that affects 1% of the population. The structural abnormalities of the brain that underlie schizophrenia are poorly understood, but they are likely to involve the axonal processes that extend outwards from neurons, and the myelin sheaths that cover these processes. We propose to extend findings of biochemical and possible structural abnormalities in myelin from autopsy brains of people with schizophrenia with new techniques that provide far more detailed information than could be obtained previously.